Michael Barza

Spectrum and Susceptibilities of Microbiologic Isolates in the Endophthalmitis Vitrectomy Study

PURPOSE To determine the microbiologic spectrum and antibiotic susceptibilities of infecting organisms in postoperative endophthalmitis and to evaluate the effects of operative factors on the microbiologic spectrum. METHODS Patients with bacterial endophthalmitis presenting within six weeks of cataract extraction or secondary intraocular lens implantation (IOL) were evaluated. Cultures and Gram stains were performed on intraocular specimens and susceptibility tests on the isolates. RESULTS Confirmed microbiologic growth was demonstrated from intraocular specimens from 291 of 420 patients (69.3%). Gram-positive bacteria were isolated from 274 patients (94.2%) with confirmed growth and gram-negative bacteria from 19 (6.5%). Two hundred twenty-six of the 323 isolates obtained (70.0%) were gram-positive, coagulase-negative micrococci, 32 (9.9%) Staphylococcus aureus, 29 (9.0%) Streptococcus species, seven (2.2%) Enterococcus species, ten (3.1%) miscellaneous gram-positive species, and 19 (5.9%) gram-negative species. All gram-positive isolates tested were susceptible to vancomycin. Seventeen gram-negative isolates (89%) were susceptible to both amikacin and ceftazidime and two (11%) were resistant to both. Anterior chamber or secondary IOL implantations were associated with higher rates of infection with gram-positives other than coagulase-negative micrococci than were posterior chamber IOL implantations (P = .022) or primary cataract extractions (P = .024). CONCLUSIONS Gram-positive, coagulase-negative micrococci predominated in this series. Vancomycin was active against all gram-positive isolates tested. Amikacin and ceftazidime showed equivalent activity against gram-negative isolates. Secondary or anterior chamber lens implantations were associated with a possible spectrum shift toward gram-positive organisms other than the coagulase-negative micrococci.

Single or multiple daily doses of aminoglycosides: a meta- analysis

Abstract Objective: To assess relative efficacy and toxicity of aminoglycosides given by single daily dose compared with multiple daily doses. Design: Meta-analysis of 21 randomised trials identified through MEDLARS (1966 to January 1995). Data were overviewed with fixed effects and random effects models and with meta-regression analysis. Subjects: Total of 3091 patients with bacterial infection, most without pre-existing renal disease. Interventions: Patients were randomised to receive aminoglycosides once daily or multiple times daily with similar total daily dose. Main outcome measures: Clinical failure of treatment, nephrotoxicity, ototoxicity, and mortality. Results: Single daily dose regimen produced a non-significant decrease in risk of antibiotic failures (random effects risk ratio 0.83 (95% confidence interval 0.57 to 1.21)). Benefit of once daily dosing was greater when the percentage of pseudomonas isolates in a trial was larger. Once daily administration reduced risk of nephrotoxicity (fixed effects risk ratio 0.74 (0.54 to 1.00)). Similar trends were noted for patients with febrile neutropenia and for children. There was no significant difference in ototoxicity between the two dosing regimens, but the power of the pooled trials to detect a meaningful difference was low. There was no significant difference in mortality. Conclusions: Once daily administration of aminoglycosides in patients without pre-existing renal impairment is as effective as multiple daily dosing, has a lower risk of nephrotoxicity, and no greater risk of ototoxicity. Given the additional convenience and reduced cost, once daily dosing should be the preferred mode of administration. Key messages Key messages This meta-analysis shows that single daily doses of aminoglycosides were about 25% less nephrotoxic than and at least as effective clinically as multiple daily doses The dosing schedule did not significantly affect the incidence of ototoxicity, but the power to detect a difference was small Once daily dosing was non-significantly more effective in patients with febrile neutropenia and in children, and the apparent benefit of once daily dosing increased with increasing proportion of pseudomonas isolates in a trial Besides the convenience of once daily dosing, reduced costs of drug administration and omission of measurements of peak antibiotic concentrations should result in substantial cost savings

Favorable Impact of a Multidisciplinary Antibiotic Management Program Conducted During 7 Years

OBJECTIVE To evaluate the impact of an interventional multidisciplinary antibiotic management program on expenditures for antibiotics and on the incidence of nosocomial infections caused by Clostridium difficile and antibiotic-resistant pathogens during 7 years. DESIGN Prospective study with comparison with preintervention trends. SETTING University-affiliated teaching hospital. PATIENTS All adult inpatients. INTERVENTION A multidisciplinary antibiotic management program to minimize the inappropriate use of third-generation cephalosporins was implemented in 1991. Its impact was evaluated prospectively. The incidence of nosocomial C. difficile and resistant Enterobacteriaceae infections as well as the rate of vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA) were compared with those of National Nosocomial Infections Surveillance System hospitals of similar size. RESULTS Following implementation of the program, there was a 22% decrease in the use of parenteral broad-spectrum antibiotics (P < .0001) despite a 15% increase in acuity of patient care during the following 7 years. Concomitantly, there was a significant (P = .002) decrease in nosocomial infections caused by C. difficile and a significant (P = .02) decrease in nosocomial infections caused by resistant Enterobacteriaceae. The program also appeared to have a favorable impact on VRE rates without a sustained impact on MRSA rates. CONCLUSION These results suggest that an ongoing multidisciplinary antibiotic management program may have a sustained beneficial impact on both expenditures for antibiotics and the incidence of nosocomial infection by C. difficile and resistant bacterial pathogens.

Efficacy of quinolone prophylaxis in neutropenic cancer patients: a meta-analysis.

PURPOSE To perform a meta-analysis to estimate the efficacy of quinolone antibiotics in preventing infections, fevers, and deaths among cancer patients neutropenic following chemotherapy. METHODS We searched MEDLINE to identify randomized trials of quinolone prophylaxis, controlled either with no prophylaxis or trimethoprim/sulfamethoxazole (TMS) prophylaxis. We pooled relative risks for outcomes using a random-effects model. RESULTS Eighteen trials with 1,408 subjects were included. Compared with no prophylaxis, quinolones significantly reduced the incidence of gram-negative bacterial infections (relative risk, 0.21; 95% confidence interval [CI], 0.12 to 0.37), microbiologically documented infections (0.65; 0.50 to 0.85), total infections (0.54; 0.31 to 0.95), and fevers (0.85; 0.73 to 0.99). Quinolone prophylaxis did not alter the incidence of gram-positive bacterial, fungal, or clinically documented infections, or infection-related deaths. Results were similar for trials that used TMS as the control regimen. Among those who received quinolones, the incidence of infections due to quinolone-resistant organisms was 3.0% (95% CI, 1.7% to 5.2%) for gram-negative species and 9.4% (95% CI, 5.3% to 16.3%) for gram-positive species. Based on limited data, the incidence of quinolone-resistant infections was not higher among quinolone recipients than controls. With fever as outcome, blinded trials found quinolones less efficacious than did unblinded trials. CONCLUSION Quinolone prophylaxis substantially reduces the incidence of various infection-related outcomes, but not deaths, in these patients. Although this reduction in infections may translate into a decrease in morbidity, the reduction in fevers (and by extension, use of empiric antibiotics) appears small, and blinded trials provided less evidence for benefit than unblinded trials. Quinolone-resistant infections are uncommon, but continued vigilance is warranted.

Relation Between Lipophilicity and Pharmacological Behavior of Minocycline, Doxycycline, Tetracycline, and Oxytetracycline in Dogs

Four tetracyclines were studied in dogs to determine the relation between their lipophilicity and various other pharmacological characteristics. Lipid solubility correlated inversely with the mean concentration of drug in arterial plasma and renal uptake and excretion, and directly with the biliary concentration gradient (level in bile/level of free drug in serum). Only the more lipophilic congeners minocycline and doxycycline passed the blood-brain and blood-ocular barriers in detectable concentrations. Mean levels of minocycline in the brain exceeded those of doxycycline by almost threefold; the difference was of borderline statistical significance (P = 0.05 to 0.1). Lipophilicity correlated inversely with the concentration of antibiotic in renal medulla but not in renal cortex or in the liver. When intestinal loops containing saline, milk, or 10% Gelusil were studied, the only combination exhibiting striking intraluminal accumulation was doxycycline in milk. These results indicate that lipophilicity correlates with many, but not all, of the transport characteristics of tetracycline antibiotics.

Effect of lipid composition and liposome size on toxicity and in vitro fungicidal activity of liposome-intercalated amphotericin B.

Intercalation of amphotericin B into liposomes at a 10 mol% drug/lipid ratio decreased its cytotoxicity by 3- to 90-fold in cultured murine cells and reduced its lethality by 2- to 8-fold in a median lethal dose (LD50) test in mice when compared with the commercial deoxycholate-solubilized drug (LD50 = 2.3 mg/kg). The cytotoxicity and lethality of the liposomal preparations were a function of their lipid composition and diameter. There was no correlation between the reduction of toxicity in the tissue culture assay and the reduction of lethality in the LD50 test. The rank order of reduction of lethality was sterol-containing liposomes greater than solid liposomes greater than fluid liposomes. In general, small sterol-containing vesicles were less lethal than large vesicles of the same composition. Intercalation of amphotericin B in sterol or solid liposomes increased not only the LD50 but also the time to death. The organ distribution of amphotericin B 24 h after intravenous administration was similar whether the drug was given as the commercial deoxycholate preparation or in liposomes. Finally, there were no differences among any of the formulations in their fungicidal activity against Candida tropicalis and Saccharomyces cerevisiae in vitro. The lesser and slower lethality of the liposomal and detergent-solubilized drug suggests that the mechanism by which liposomes reduce the lethality of amphotericin B is by slowing its rate of transfer to a sensitive cellular target.

Past and current roles for cephalosporin antibiotics in treatment of meningitis: Emphasis on use in gram-negative bacillary meningitis

The therapy of gram-negative bacillary meningitis is less than adequate to date; the agents recommended do not achieve bactericidal levels in purulent cerebrospinal fluid. Because optimal antibiotic therapy of meningitis occurs when the cerebrospinal fluid level of an antibiotic is above the concentration needed to kill the offending pathogen, another group of agents needs to be considered. The newer cephalosporins or cehalosporin-type antibiotics (cefotaxime, moxalactam), by virtue of their marked activity against gram-negative bacilli and their ability to achieve significant CSF levels, merit serious consideration as therapy for gram-negative bacillary meningitis. Investigators in Europe and the United States have developed preliminary data demonstrating the efficacy of these agents in a growing number of cases. In the group presented herein, of the 35 cases in which gram-negative bacillary meningitis was treated with the newer cephalosporins, there were only four failures.

Why monitor serum levels of gentamicin

SummaryAlthough it is widely recommended that serum levels of aminoglycoside antibiotics be monitored by assay, the justification for this approach has not been clearly presented. A number of studies indicate that serum levels of these agents cannot be predicted reliably on the basis of simple dosage formulae; the major confounding factors being abnormalities of renal function and of extracellular fluid volume in addition to less well defined variables such as fever and anaemia. The influence of haemodialysis and concomitant administration of carbenicillin further complicate dosage estimations in patients with renal insufficiency.On the basis of currently available data, it is reasonable to suggest an optimum range of 5 to 8μg/ml for peak serum levels of gentamicin. There are no reliable studies from which to derive a comparable value for trough (pre-dose) concentrations. The relative importance of peak and trough values for nephrotoxicity and ototoxicity is an unresolved subject of controversy. However, it seems possible that neither of these individual values, but rather the ‘area under the time-concentration curve’ is the major risk factor for toxicity.In view of the unpredictability of serum levels, especially in seriously ill patients in a fluctuating physiological state, periodical serum gentamicin assays should be performed. The main objective of these assays is to ensure that the peak serum levels attained are adequate, but not unnecessarily high.

Are amoxycillin and folate inhibitors as effective as other antibiotics for acute sinusitis? A meta-analysis

Abstract Objectives: To examine whether antibiotics are indicated in treating uncomplicated acute sinusitis and, if so, whether newer and more expensive antibiotics with broad spectra of antimicrobial activity are more effective than amoxycillin or folate inhibitors. Design: Meta-analysis of randomised trials. Setting: Outpatient clinics. Subjects: 2717 patients with acute sinusitis or acute exacerbation of chronic sinusitis from 27 trials. Interventions: Any antibiotic versus placebo; amoxycillin or folate inhibitors versus newer, more expensive antibiotics. Main outcome measurements: Clinical failures and cures. Results: Compared with placebo, antibiotics decreased the incidence of clinical failures by half (risk ratio 0.54 (95% confidence interval 0.37 to 0.79)). Risk of clinical failure among 1553 randomised patients was not meaningfully decreased with more expensive antibiotics as compared with amoxycillin (risk ratio 0.86 (0.62 to 1.19); risk difference 0.9 fewer failures per 100 patients (1.4 more failures to 3.1 fewer failures per 100 patients)). The results were similar for other antibiotics versus folate inhibitors (risk ratio 1.01 (0.52 to 1.97)), but data were sparse (n=410) and of low quality. Conclusions: Amoxycillin and folate inhibitors are essentially as effective as more expensive antibiotics for the initial treatment of uncomplicated acute sinusitis. Small differences in efficacy may exist, but are unlikely to be clinically important.

Meta-analysis of diagnostic tests for acute sinusitis

To facilitate management of acute sinusitis, we conducted a meta-analysis of published studies comparing diagnostic tests for this disorder. Thirteen studies were identified through literature search. Based on sinus puncture/aspiration (considered most accurate), 49-83% of symptomatic patients had acute sinusitis. Compared with puncture/aspiration, radiography offered moderate ability to diagnose sinusitis (summary receiver operator curve [SROC] area, 0.83). Using sinus opacity or fluid as the criterion for sinusitis, radiography had sensitivity of 0.73 and specificity of 0.80. Studies evaluating ultrasonography revealed substantial variation in test performance. The clinical evaluation, particularly risk scores formally incorporating history and physical examination findings, had moderate ability to identify patients with positive radiographs (SROC area, 0.74). Many studies were of poor quality, with inadequately described test methods and unblinded test interpretation. In conclusion, acute sinusitis is common among symptomatic patients. Radiography and clinical evaluation (especially risk scores) appear to provide useful information for diagnosis of sinusitis.